Phase III double-blind randomized trial of radiation therapy for stage IIIB cervical cancer in combination with low or high dose Z-100, immunomodulator widely used in Japan

Abstract

5029 Background: The Specific Substance of Maruyama (SSM) is a well-known immunomodulator that has been used in Japan as an unapproved drug in the treatment of over 240,000 cancer-bearing patients since 1970. Z-100 is the same agent as SSM, used in different concentrations. The aim of this study is to investigate whether Z-100 enhances the efficacy of radiation therapy (RT) for locally advanced cervical cancer of the uterus. Methods: Between 1995 and 1999, 221 (217 evaluable) patients with stage IIIb squamous cell carcinoma of the uterine cervix were randomly assigned to treatment with either 0.2 μg Z-100 (Group L: n=109) or 40 μg Z-100 (Group H: n=108) in a double-blind manner in combination with conventional RT. Z-100 was administered twice a week during the RT, and it was continuously administered every two weeks after RT for as long as possible ≥ 2 years, or until recurrence or progression was noted. The endpoints were tumor response, progression-free survival (PFS) and overall survival (OS). Results: There was no difference in the tumor-regression effect of Z-100 between two groups. The 5-year survival of Group H was 41.5%, (95%CI: 31.7–51.3%), which was equivalent to that of Japanese historical controls treated by RT alone (35–42%), or to the 4-year survival rate of the RT plus hydroxyurea arms of GOG120 study (50%). The 5-year survival of Group L was 58.2% (95% CI: 48.7–67.7%). Compared with Group H, Group L showed a 30% reduction in the death rate (hazard ratio: 0.670 [95% CI: 0.458 - 0.980], log-rank test, p=0.0387). PFS was also significantly improved in favor of Group L (hazard ratio: 0.667 [95% CI: 0.447 - 0.997], p=0.0482). OS and PFS of Group L were equivalent to those of concurrent cisplatin-based chemoradiation arms of the GOG study. Conclusions: It was suggested that RT combined with the immunomodulator Z-100 improved the survival of patients with locally advanced cervical cancer. However, more was not better, suggesting that the dose response to immunomodulators is different from the responses to conventional cytotoxic agents. A randomized placebo controlled trial is under planning. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Zeria Pharmaceuticals Aventis; Bristol; GlaxoSmithKline; Roche; AstraZeneca; Zeria